4-165088507-C-G

Variant names:

• chr4-165088507-C-G
• NM_001100389.2:c.535G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001100389.2(TMEM192):​c.535G>C​(p.Glu179Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM192 NM_001100389.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.95

Genes affected

TMEM192 (HGNC:26775): (transmembrane protein 192) Enables protein homodimerization activity. Located in several cellular components, including late endosome; lysosomal membrane; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM192	NM_001100389.2	c.535G>C	p.Glu179Gln	missense_variant	Exon 4 of 6	ENST00000306480.11	NP_001093859.1
TMEM192	XM_011531718.4	c.440-2819G>C		intron_variant	Intron 3 of 4		XP_011530020.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM192	ENST00000306480.11	c.535G>C	p.Glu179Gln	missense_variant	Exon 4 of 6	1	NM_001100389.2	ENSP00000305069.4
TMEM192	ENST00000506087.5	c.523G>C	p.Glu175Gln	missense_variant	Exon 5 of 7	2		ENSP00000425335.1
TMEM192	ENST00000505095.1	c.112G>C	p.Glu38Gln	missense_variant	Exon 5 of 6	3		ENSP00000424590.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535G>C (p.E179Q) alteration is located in exon 4 (coding exon 4) of the TMEM192 gene. This alteration results from a G to C substitution at nucleotide position 535, causing the glutamic acid (E) at amino acid position 179 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.85
MutPred		0.65		Gain of catalytic residue at C182 (P = 0.1242);.;.;
MVP		0.20
MPC		0.15
ClinPred		0.96	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166009659;